<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "The malate aspartate shuttle in T cell metabolic fitness:\r\nGlutamic oxaloacetic transaminase 1\r\nantagonizes T cell exhaustion"^^ . "CD8+ T cells play a crucial role in fighting infectious diseases and cancers, but it is frequently\r\nobserved that CD8+ T cells are functionally compromised or “exhausted” in chronic infections\r\nand solid tumors. Exhausted T cells are characterized by the expression of immune checkpoint\r\nmolecules, reduction in effector cytokine secretion, and alterations in cellular metabolism, such\r\nas loss of mitochondrial membrane potential (ΔΨm). Immune checkpoint blockade-based\r\nimmunotherapies revive exhausted T cells, enhance effector cytokine production, and have\r\nachieved clinical success in several types of cancers. It is unknown whether and how ΔΨm\r\nregulates T cell exhaustion in chronic infection and cancer. Mitochondrial complexes accept\r\nelectrons from tricarboxylic acid (TCA) cycle-derived electron carriers, transfer electrons, and\r\npump protons to establish a membrane potential. The malate aspartate shuttle (MAS)\r\nproduces and transports electron carriers into the mitochondrial matrix and donates electrons\r\nto the electron transport chain (ETC). We, therefore, hypothesize that MAS may regulate ΔΨm\r\nand antagonize T cell exhaustion.\r\nTo test this hypothesis, we have generated a mouse model with T cell-specific deficiency of\r\nglutamic oxaloacetic transaminase 1 (Got1, encoding the MAS enzyme GOT1). We chose\r\nGOT1 because it is a key enzyme of the MAS, and we observed that GOT1 expression was\r\ninduced by persistent antigenic stimulation in mouse CD8+ T cells and upregulated in CD8+\r\ntumor-infiltrating lymphocytes (TILs) from human colon cancer. T cell-specific ablation of Got1\r\nimpaired tumor-specific effector CD8+ T cell accumulation, effector cytokine production and\r\npotential to sustain long term immune responses in a mouse melanoma model. Using the\r\nlymphocytic choriomeningitis virus (LCMV) Armstrong acute infection and the LCMV clone 13\r\nchronic infection model, we found that Got1 deficiency affected the ongoing antiviral effector\r\nresponses, but not the memory T cell formation after viral clearance, suggesting that CD8+\r\nresponses required GOT1 in the presence of persistent, but not transient antigenic stimulation.\r\nFurther analysis revealed that Got1 deficiency alone did not affect CD8+ T cell metabolism or\r\nΔΨm when cells were cultured in complete medium. Instead, Got1 deficiency became only\r\ncatastrophic for CD8+ T cells when extracellular nutrients were restricted, and antigenic\r\nstimulation was persistent. Got1 deficiency reduced the NAD+/NADH ratio, increased reactive\r\noxygen species (ROS) production and decreased ΔΨm. This study reveals, GOT1 selectively\r\nsupports effector CD8+ T cells that are nutrient restricted and chronically stimulated.\r\nSummarized, the presented work revealed that persistent stimulation with tumor and viral\r\nantigens induced GOT1 expression on CD8+ T cells. GOT1 was shown to desensitize CD8+ T\r\ncells to environmental nutrient limitation and persistent antigenic stimulation-induced loss of\r\nΔΨm and T cell exhaustion. These results present an example of how immune cells alter their\r\nmetabolic pathways to adapt to nutrient and antigen availability."^^ . "2020" . . . . . . . "Nina Kathrin"^^ . "Weißhaar"^^ . "Nina Kathrin Weißhaar"^^ . . . . . . "The malate aspartate shuttle in T cell metabolic fitness:\r\nGlutamic oxaloacetic transaminase 1\r\nantagonizes T cell exhaustion (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "The malate aspartate shuttle in T cell metabolic fitness:\r\nGlutamic oxaloacetic transaminase 1\r\nantagonizes T cell exhaustion (Other)"^^ . . . . . . "small.jpg"^^ . . . "The malate aspartate shuttle in T cell metabolic fitness:\r\nGlutamic oxaloacetic transaminase 1\r\nantagonizes T cell exhaustion (Other)"^^ . . . . . . "preview.jpg"^^ . . . "The malate aspartate shuttle in T cell metabolic fitness:\r\nGlutamic oxaloacetic transaminase 1\r\nantagonizes T cell exhaustion (Other)"^^ . . . . . . "medium.jpg"^^ . . . "The malate aspartate shuttle in T cell metabolic fitness:\r\nGlutamic oxaloacetic transaminase 1\r\nantagonizes T cell exhaustion (PDF)"^^ . . . "Thesis_Weisshaar.pdf"^^ . . . "The malate aspartate shuttle in T cell metabolic fitness:\r\nGlutamic oxaloacetic transaminase 1\r\nantagonizes T cell exhaustion (Other)"^^ . . . . . "HTML Summary of #28814 \n\nThe malate aspartate shuttle in T cell metabolic fitness: \nGlutamic oxaloacetic transaminase 1 \nantagonizes T cell exhaustion\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . . . "610 Medizin"@de . "610 Medical sciences Medicine"@en . .